Pneumocystis Carinii Pneumonia—Problems in Diagnosis and Therapy in 24 Cases

Twenty-four instances of Pneumocystis carinii pneumonia were recognized in 23 patients at the Stanford University Hospitals between 1962 and 1970. The affected persons could be broadly characterized as “compromised” hosts. All but one were receiving immunosuppressive drug therapy for such underlying disease as hematopoietic malignant disease, collagen vascular disorder, and organ transplant rejection. The one patient not receiving immunosuppressant medication had congenital dysgammaglobulinemia and suffered two discrete bouts of pneumocystis pneumonia. Most of the patients were concomitantly infected with other “opportunistic” pathogens.Open lung biopsy remained the most reliable method of antemortem diagnosis of pneumocystis infection during this eight-year period. It resulted in little morbidity. Unfortunately, direct examination of appropriately stained sputum specimens for cysts was almost uniformly nonproductive.The majority of patients received specific antipneumocystis drug treatment (pentamidine isethionate or pyrimethamine and sulfadiazine). “Cure” was achieved when institution of therapy was prompt and duration of therapy approached the empirically recommended two-week course.The fact that pneumocystis pneumonia can be controlled if recognized early is compelling reason to pursue diagnosis of pneumocystosis in an appropriate clinical setting, namely, in patients with impaired host defenses who have pulmonary infection unresponsive to conventional therapy. There is hope that a noninvasive (serological) technique will be developed shortly to simplify identification of this not uncommon cause of diffuse interstitial pneumonitis.     

Validity of Antibodies in Lymphocyte Supernatant in Diagnosing Tuberculosis in Severely Malnourished Children Presenting with Pneumonia

BackgroundThe diagnosis of tuberculosis (TB) in young children can be challenging, especially in severely malnourished children. There is a critical need for improved diagnostics for children. Thus, we sought to evaluate the performance of a technique that measures antibodies in lymphocyte supernatant (ALS) for the diagnosis of TB in severely malnourished children presenting with suspected pneumonia.MethodsChildren less than 5 years with severe acute malnutrition and radiological features of pneumonia admitted to the Dhaka Hospital of International Centre for Diarrhoeal Disease Research, Bangladesh, were enrolled consecutively following informed written consent. In addition to clinical and radiological assessment, samples taken for TB diagnosis included gastric lavage fluid and induced sputum for microbiological confirmation. ALS was measured from venous blood, and results were evaluated in children classified as “confirmed”, “non-confirmed TB” or “not TB”.ResultsAmong 224 children who had ALS analysis, 12 (5.4%) children had microbiologically “confirmed TB”, a further 41 (18%) had clinically diagnosed “non-confirmed TB” and the remaining 168 (75%) were considered not to have TB. ALS was positive in 89 (40%) and negative in 85 (39%) of children, with a large number (47 or 21%) reported as “borderline”. These proportions were similar between the three diagnostic groups. The sensitivity and specificity of ALS when comparing “Confirmed TB” to “Not TB” was only 67% (95% CI: 31–91%) and 51% (95% CI: 42–60%), respectively.

Conclusions and Significance

Our data suggest that ALS is not sufficiently accurate to improve the diagnosis of TB in children with severe malnutrition.     

Association between Mouth Breathing and Atopic Dermatitis in Japanese Children 2–6 years Old: A Population-Based Cross-Sectional Study

As mouth breathing is associated with asthma and otitis media, it may be associated with other diseases. Therefore, this population-based cross-sectional study evaluated the association of mouth breathing with the prevalences of various diseases in children. Preschool children older than 2 years were included. A questionnaire was given to parents/guardians at 13 nurseries in Tokushima City. There were 468 valid responses (45.2%). We defined a subject as a mouth breather in daytime (MBD) if they had 2 or more positive items among the 3 following items: “breathes with mouth ordinarily,” “mouth is open ordinarily,” and “mouth is open when chewing.” We defined subjects as mouth breathers during sleep (MBS) if they had 2 or more positive items among the following 3 items: “snoring,” “mouth is open during sleeping,” and “mouth is dry when your child gets up.” The prevalences of MBD and MBS were 35.5% and 45.9%, respectively. There were significant associations between MBD and atopic dermatitis (odds ratio [OR]: 2.4, 95% confidence interval [CI]: 1.4–4.2), MBS and atopic dermatitis (OR: 2.4, 95% CI: 1.3–4.2), and MBD and asthma (OR: 2.2, 95% CI: 1.2–4.0). After adjusting for history of asthma and allergic rhinitis; family history of atopic dermatitis, asthma, and allergic rhinitis; and nasal congestion; both MBD (OR: 2.6, 95% CI: 1.3–5.4) and MBS (OR: 4.1, 95% CI: 1.8–9.2) were significantly associated with atopic dermatitis. In preschool children older than 2 years, both MBD and MBS may be associated with the onset or development of atopic dermatitis.     

Antibiotic sensitivities of Neisseria gonorrhoeae in the Toronto area

The antibiotic sensitivity pattern of 3872 isolates of N. gonorrhoeae tested in Toronto from 1969 to 1973 is reviewed. An increase in resistance to both penicillin and tetracycline was noted up to 1971, but no further increase has occurred since then. Ninety-seven percent of 135 patients with “sensitive” strains (inhibited by 0.3 U/ml of penicillin and/or 0.5 μg/ml of tetracycline) were cured by either 8 g of tetracycline or 5,000,000 U of penicillin, whereas only 59% of 58 patients with “resistant” strains (requiring 1.0 U/ml of penicillin and/or 2.0 μg/ml of tetracycline for inhibition) were cured by the same dosage. Spectinomycin appears to be an acceptable alternative therapy. Maximum doses of the chosen drug are recommended in the hope of retarding further spread of more resistant organisms.     

Is Early Tuberculosis Death Associated with Increased Tuberculosis Transmission?

Introduction

Tuberculosis (TB) is now a relatively uncommon disease in high income countries. As such, its diagnosis may be missed or delayed resulting in death before or shortly after the introduction of treatment. Whether early TB death is associated with increased TB transmission is unknown. To determine the transmission risk attributable to early TB death we undertook a case-control study.

Methods

All adults who were: (1) diagnosed with culture-positive pulmonary TB in the Province of Alberta, Canada between 1996 and 2012, and (2) died a TB-related death before or within the first 60 days of treatment, were identified. For each of these “cases” two sets of “controls” were randomly selected from among culture-positive pulmonary TB cases that survived beyond 60 days of treatment. “Controls” were matched by age, sex, population group, +/- smear status. Secondary cases of “cases” and “controls” were identified using conventional and molecular epidemiologic tools and compared. In addition, new infections were identified and compared in contacts of “cases” that died before treatment and contacts of their smear-matched “controls”. Conditional logistic regression was used to find associations in both univariate and multivariate analysis.

Results

“Cases” were as, but not more, likely than “controls” to transmit. This was so whether transmission was measured in terms of the number of “cases” and smear-unmatched or -matched “controls” that had a secondary case, the number of secondary cases that they had or the number of new infections found in contacts of “cases” that died before treatment and their smear-matched “controls”.

Conclusion

In a low TB incidence/low HIV prevalence country, pulmonary TB patients that die a TB-related death before or in the initial phase of treatment and pulmonary TB patients that survive beyond the initial phase of treatment are equally likely to transmit.     

Direct Observation (DO) for Drug-Resistant Tuberculosis: Do We Really DO?

Introduction

Directly-observed therapy (DOT) is recommended for drug-resistant tuberculosis (DR-TB) patients during their entire treatment duration. However, there is limited published evidence on implementation of direct observation (DO) in the field. This study aims to detail whether DO was followed with DR-TB patients in a Médecins Sans Frontières (MSF) tuberculosis program in Mumbai, India.

Methods

This was a cross-sectional, mixed-methods study. Existing qualitative data from a purposively-selected subset of 12 patients, 5 DOT-providers and 5 family members, were assessed in order to determine how DO was implemented. A questionnaire-based survey of DR-TB patients, their DOT-providers and MSF staff was completed between June and August 2014. Patients were defined as”following Strict DO” and “following DO” if a DOT-provider had seen the patient swallow his/her medications “every day” or “most of the days” respectively. If DO was not followed, reasons were also recorded. The qualitative data were analysed for theme and content and used to supplement the questionnaire-based data.

Results

A total of 70 DR-TB patients, 65 DOT-providers and 21 MSF health staff were included. Fifty-five per cent of the patients were HIV-co-infected and 41% had multidrug-resistant-TB plus additional resistance to a fluoroquinolone. Among all patients, only 14% (10/70) and 20% (14/70) self-reported “following Strict DO” and “following DO” respectively. Among DOT-providers, 46% (30/65) reported that their patients “followed DO”. MSF health staff reported none of the patients “followed DO”. Reasons for not implementing DO included the unavailability of DOT-provider, time spent, stigma and treatment adverse events. The qualitative data also revealed that “Strict DO” was rarely followed and noted the same reasons for lack of implementation.

Conclusion

This mixed-methods study has found that a majority of patients with DR-TB in Mumbai did not follow DO, and this was reported by patients and care-providers. These data likely reflect the reality of DO implementation in many high-burden settings, since this relatively small cohort was supported and closely monitored by a skilled team with access to multiple resources. The findings raise important concerns about the necessity of DO as a “pillar” of DR-TB treatment which need further validation in other settings. They also suggest that patient-centred adherence strategies might be better approaches for supporting patients on treatment.     

Total infectome characterization of respiratory infections in pre-COVID-19 Wuhan,China

At the end of 2019 Wuhan witnessed an outbreak of “atypical pneumonia” that later developed into a global pandemic. Metagenomic sequencing rapidly revealed the causative agent of this outbreak to be a novel coronavirus denoted SARS-CoV-2. To provide a snapshot of the pathogens in pneumonia-associated respiratory samples from Wuhan prior to the emergence of SARS-CoV-2, we collected bronchoalveolar lavage fluid samples from 408 patients presenting with pneumonia and acute respiratory infections at the Central Hospital of Wuhan between 2016 and 2017. Unbiased total RNA sequencing was performed to reveal their “total infectome”, including viruses, bacteria and fungi. We identified 35 pathogen species, comprising 13 RNA viruses, 3 DNA viruses, 16 bacteria and 3 fungi, often at high abundance and including multiple co-infections (13.5%). SARS-CoV-2 was not present. These data depict a stable core infectome comprising common respiratory pathogens such as rhinoviruses and influenza viruses, an atypical respiratory virus (EV-D68), and a single case of a sporadic zoonotic pathogen–Chlamydia psittaci. Samples from patients experiencing respiratory disease on average had higher pathogen abundance than healthy controls. Phylogenetic analyses of individual pathogens revealed multiple origins and global transmission histories, highlighting the connectedness of the Wuhan population. This study provides a comprehensive overview of the pathogens associated with acute respiratory infections and pneumonia, which were more diverse and complex than obtained using targeted PCR or qPCR approaches. These data also suggest that SARS-CoV-2 or closely related viruses were absent from Wuhan in 2016–2017.     

Psychiatric Illness in General Practice: A Detailed Study Using a New Method of Case Identification

A self-administered questionary (the General Health Questionnaire) aimed at detecting current psychiatric disturbance was given to 553 consecutive attenders to a general practitioner''s surgery. A sample of 200 of these patients was given an independent assessment of their mental state by a psychiatrist using a standardized psychiatric interview. Over 90% of the patients were correctly classified as “well” or “ill” by the questionary, and the correlation between questionary score and the clinical assessment of severity of disturbance was found to be +0·80.The “conspicuous psychiatric morbidity” of a suburban general practice assessed by a general practitioner who was himself a psychiatrist and validated against independent psychiatric assessment was found to be 20%. “Hidden psychiatric morbidity” was found to account for one-third of all disturbed patients. These patients were similar to patients with “conspicuous illnesses” in terms both of degree of disturbance and the course of their illnesses at six-month follow-up, but were distinguished by their attitude to their illness and by usually presenting a physical symptom to the general practitioner.When 87 patients who had been assessed as psychiatric cases at the index consultation were called back for follow-up six months later, two-thirds of them were functioning in the normal range. Frequency of attendance at the surgery in the six months following index consultation was found to have only a modest relationship to severity of psychiatric disturbance.It is argued that minor affective illnesses and physical complaints often accompany each other and usually have a good prognosis.     

RESISTANT URINARY TRACT INFECTIONS—Combined Autogenous Vaccine and Drug Therapy

The “miracle” antibiotics and sulfa drugs have been found unsatisfactory in treating certain severe resistant urinary tract infections apparently due to lack of immunity factor in the patient. Of a series of 56 patients with resistant urinary tract infection who were treated with autogenous vaccine and then with sulfa drugs, 26 were completely cured.     

Recognition of Leukaemia Cells as Foreign before and after Autoimmunization

Leukaemia cells in the peripheral blood of nine patients with acute leukaemia were removed and stored. When the patients had been brought into haematological remission these leukaemia cells were cultured with autologous lymphocytes both before and after the patients had been autoimmunized with their own irradiated leukaemia cells. The extent to which the leukaemia cells stimulated the “normal lymphocytes” was increased as the result of autoimmunization.The implications of the use of this test for determining the best regimen for “immunotherapy” in acute leukaemia are discussed.     

Accelerated Wound Closure In Vitro by Fibroblasts from a Subgroup of Cleft Lip/Palate Patients: Role of Transforming Growth Factor-α

In a fraction of patients surgically treated for cleft lip/palate, excessive scarring disturbs maxillary growth and dento-alveolar development. Since certain genes are involved in craniofacial morphogenesis as well as tissue repair, a primary defect causing cleft lip/palate could lead to altered wound healing. We performed in vitro wound healing assays with primary lip fibroblasts from 16 cleft lip/palate patients. Nine foreskin fibroblast strains were included for comparison. Cells were grown to confluency and scratch wounds were applied; wound closure was monitored morphometrically over time. Wound closure rate showed highly significant differences between fibroblast strains. Statistically, fibroblast strains from the 25 individuals could be divided into three migratory groups, namely “fast”, “intermediate”, and “slow”. Most cleft lip/palate fibroblasts were distributed between the “fast” (5 strains) and the “intermediate” group (10 strains). These phenotypes were stable over different cell passages from the same individual. Expression of genes involved in cleft lip/palate and wound repair was determined by quantitative PCR. Transforming growth factor-α mRNA was significantly up-regulated in the “fast” group. 5 ng/ml transforming growth factor-α added to the culture medium increased the wound closure rate of cleft lip/palate strains from the “intermediate” migratory group to the level of the “fast”, but had no effect on the latter group. Conversely, antibody to transforming growth factor-α or a specific inhibitor of its receptor most effectively reduced the wound closure rate of “fast” cleft lip/palate strains. Thus, fibroblasts from a distinct subgroup of cleft lip/palate patients exhibit an increased migration rate into wounds in vitro, which is linked to higher transforming growth factor-α expression and attenuated by interfering with its signaling.     

The Metabolism of the Volatile Amines: VII. The Clinical Significance of Two Components of the Blood Ammonia Level

Blood ammonia levels consist of two components: ammonia present in blood at the time of shedding, termed “free” ammonia, and ammonia produced by the deamidating action of the alkali reagents. Blood of healthy people contained little or no “free” ammonia while blood of patients with chronic liver disease occasionally showed levels up to 1.2 μg./ml. Patients with hepatic encephalopathy had significantly elevated levels which usually fell to zero following therapy. Levels of “free” ammonia above 0.6 μg./ml. were diagnostic of hepatic encephalopathy in patients suffering from unexplained neurological disorders.The rate of formation of ammonia by the alkali reagents was increased in patients with hepatic necrosis and was depressed in those with chronic hepatitis. The ammonia appeared to arise from the deamidation of glutamine and asparagine, present in blood in both the free and peptide forms.     

The Association between the Use of Proton Pump Inhibitors and the Risk of Hypomagnesemia: A Systematic Review and Meta-Analysis

Background

Although many case reports have described patients with proton pump inhibitor (PPI)-induced hypomagnesemia, the impact of PPI use on hypomagnesemia has not been fully clarified through comparative studies. We aimed to evaluate the association between the use of PPI and the risk of developing hypomagnesemia by conducting a systematic review with meta-analysis.

Methods

We conducted a systematic search of MEDLINE, EMBASE, and the Cochrane Library using the primary keywords “proton pump,” “dexlansoprazole,” “esomeprazole,” “ilaprazole,” “lansoprazole,” “omeprazole,” “pantoprazole,” “rabeprazole,” “hypomagnesemia,” “hypomagnesaemia,” and “magnesium.” Studies were included if they evaluated the association between PPI use and hypomagnesemia and reported relative risks or odds ratios or provided data for their estimation. Pooled odds ratios with 95% confidence intervals were calculated using the random effects model. Statistical heterogeneity was assessed with Cochran’s Q test and I ² statistics.

Results

Nine studies including 115,455 patients were analyzed. The median Newcastle-Ottawa quality score for the included studies was seven (range, 6–9). Among patients taking PPIs, the median proportion of patients with hypomagnesemia was 27.1% (range, 11.3–55.2%) across all included studies. Among patients not taking PPIs, the median proportion of patients with hypomagnesemia was 18.4% (range, 4.3–52.7%). On meta-analysis, pooled odds ratio for PPI use was found to be 1.775 (95% confidence interval 1.077–2.924). Significant heterogeneity was identified using Cochran’s Q test (df = 7, P<0.001, I ² = 98.0%).

Conclusions

PPI use may increase the risk of hypomagnesemia. However, significant heterogeneity among the included studies prevented us from reaching a definitive conclusion.     

Foetal Blood Sampling. Practical Approach to Management of Foetal Distress

The practical application of foetal blood sampling in the routine management of patients in labour has been reviewed in a six-month survey, during which time 1,668 patients were delivered at Queen Charlotte''s Hospital.Foetal acidaemia (pH 7·25 or less) occurred in 45 of the 295 patients who showed clinical signs of foetal distress. Foetal tachycardia was the presenting sign in 33 of these 45 patients, underlining the importance of this physical sign. Foetal acidaemia in association with clinical foetal distress occurred twice as often in patients who had complications of pregnancy and who were therefore regarded as obstetrically “at risk” as it did in patients who were obstetrically “normal” No cases of acidaemia were detected in any of the foetal blood samples performed routinely on “at-risk” patients in the absence of clinical foetal distress.     

Hospital Infections Caused by a Group of Recently Recognized Strains of Staphylococcus aureus

A survey was made of the phage-types of staphylococci responsible for cross-infection in a large veterans'' hospital between 1961 and 1964. An earlier survey had shown that in 1959 most of the infections were caused by staphylocci of the “80/81/82” group. In 1961 a new group of staphylococci were first recognized and provisionally designated as “Atypical Group III” strains; these were non-typable by the usual typing phages but showed inhibition patterns with some of the Group III phages. The “Atypical Group III” staphylococci all showed one or other of four patterns of multiple antibiotic resistance. By 1963 these resistant “Atypical Group III” staphylococci had become more frequent than “80/81/82” strains as causative agents of cross-infection, although both groups have continued to cause infections in the hospital. “Atypical Group III” strains mainly infected surgical wounds and skin ulcers, whereas “80/81/82” strains commonly produced primary skin sepsis, such as boils.     

Beneficial Effect of Isoniazid Preventive Therapy and Antiretroviral Therapy on the Incidence of Tuberculosis in People Living with HIV in Ethiopia

Background

IPT with or without concomitant administration of ART is a proven intervention to prevent tuberculosis among PLHIV. However, there are few data on the routine implementation of this intervention and its effectiveness in settings with limited resources.

Objectives

To measure the level of uptake and effectiveness of IPT in reducing tuberculosis incidence in a cohort of PLHIV enrolled into HIV care between 2007 and 2010 in five hospitals in southern Ethiopia.

Methods

A retrospective cohort analysis of electronic patient database was done. The independent effects of no intervention, “IPT-only,” “IPT-before-ART,” “IPT-and-ART started simultaneously,” “ART-only,” and “IPT-after-ART” on TB incidence were measured. Cox-proportional hazards regression was used to assess association of treatment categories with TB incidence.

Results

Of 7,097 patients, 867 were excluded because they were transferred-in; a further 823 (12%) were excluded from the study because they were either identified to have TB through screening (292 patients) or were on TB treatment (531). Among the remaining 5,407 patients observed, IPT had been initiated for 39% of eligible patients. Children, male sex, advanced disease, and those in Pre-ART were less likely to be initiated on IPT. The overall TB incidence was 2.6 per 100 person-years. As compared to those with no intervention, use of “IPT-only” (aHR = 0.36, 95% CI = 0.19–0.66) and “ART-only” (aHR = 0.32, 95% CI = 0.24–0.43) were associated with significant reduction in TB incidence rate. Combining ART and IPT had a more profound effect. Starting IPT-before-ART (aHR = 0.18, 95% CI = 0.08–0.42) or simultaneously with ART (aHR = 0.20, 95% CI = 0.10–0.42) provided further reduction of TB at ∼80%.

Conclusions

IPT was found to be effective in reducing TB incidence, independently and with concomitant ART, under programme conditions in resource-limited settings. The level of IPT provision and effectiveness in reducing TB was encouraging in the study setting. Scaling up and strengthening IPT service in addition to ART can have beneficial effect in reducing TB burden among PLHIV in settings with high TB/HIV burden.     

The Histological Components of the Phoniatrical Body-Cover Model in Minipigs of Different Ages

Pigs are models in human phoniatry. However, features of maturation and ageing have not been considered with regard to the so-called body-cover model in this species. Therefore, the glottis of “young” (2–3 months; n = 6) and “old” (4–7 years; n = 6) minipigs was investigated. Their cranial (CraF) and caudal (CauF) vocal folds were histomorphometrically and stratigraphically analysed with emphasis on their amounts of collagen structures and elastic fibres. A dense subepithelial layer (SEL) was a distinct feature of CraF and CauF of both age groups; it was spread upon the underlying loose, flexible “cover” like a fibro-elastic membrane. The “cover” was characterised by the so-called superficial layer (SL), which was distinctly loose in the “young” minipigs, but had a much denser texture in the “old” minipigs. Here, the SL was dominated by elastic fibres in the CraF, but was of mixed qualities (collagenous and elastic) in the CauF. The structural requirements for the SL’s function as a loose “cover” were thus met only in the “young” animals. A clearly demarcated intermediate layer (IL)—characterised by high amounts of elastic fibres (as in humans)—was only found in the CraF of the “young” animals. In the “old” animals, it had lost its demarcation. In the depth of the CraF of the “old” animals, many thick collagen fibre bundles were detected in a location equivalent to that of the vocal muscle in the CauF. The development of their large diameters was interpreted as part of the maturation process, thereby supporting the hypothesis of their functional importance as a component of the “body.” In the CauF, the amounts of collagen structures increased throughout the entire lamina propria, resulting in a loss of demarcated stratigraphical subdivisions in the “old” minipigs. This situation resembled that described in the vocal fold of geriatric humans.     

USE OF THE ARTIFICIAL KIDNEY—Its Place in the Treatment of Acute Renal Failure

Of 57 patients with severe, but potentially reversible, acute renal failure who were observed during a recent four-year period, some had dialysis with an artificial kidney and some did not.Twenty survived with the standard “conservative” management alone; 19 survived with a combination of “conservative” and “intensive” (that is, artificial kidney) treatment; 18 patients died.One error that was made in the management of all 18 patients who died, was excessive delay in the use of the artificial kidney.Hemodialysis should be used whenever serious electrolyte abnormality exists, whenever the blood urea nitrogen exceeds 150 mg. per 100 cc. or whenever clinical signs of uremia first appear. One or more of these indications will usually, but not always, become evident between the fifth and the eighth day of virtual anuria.     

Secondary Respiratory Infection in Hospital Patients: Effect of Antimicrobial Agents and Environment

A prospective study of 358 medical and 234 postoperative patients with clinical evidence of secondary chest infection showed that previous administration of antimicrobial agents greatly reduced the chance of obtaining a clear-cut laboratory report. In patients with radiographical evidence of pneumonia this led to a fourfold decrease in the overall rate of isolation of potential pathogens. Furthermore, 81 diverse “coliforms” were isolated from 258 medical and surgical patients who had received previous antimicrobial therapy while only four coliforms (all Escherichia coli) were isolated from 334 untreated patients. Thus the general hospital environment on its own seemed to have a negligible influence in promoting the growth of coliform flora in sputum. Any unique effect of underlying disease in this regard was masked by that of previous therapy. Finally, the results raised the possibility that previous antimicrobial therapy might have increased the risk of secondary pneumonia in hospital patients.